Age-related macular degeneration (AMD) remains a major cause of blindness in the industrial world (1). The frequency of AMD increases with age, affecting 2% of the population at age 50, and 25% by age 80; and affects as many as 1.5 million Americans, and millions more around the world. There are two forms of AMD: “dry” and “wet”. Dry AMD affects 85-90% of people with AMD, and is a chronic, asymptomatic disease that at the early stages may cause some degree of visual impairment, and may progress to legal blindness in the advanced stage of the disease. In the early stages of dry AMD, insoluble extracellular aggregates called drusen accumulate in the retina and are associated with decreased vision (1). The late stage of dry AMD, also known as geographic atrophy (GA), is characterized by scattered or confluent areas of degeneration of retinal pigment epithelial (RPE) cells and the overlying light-sensing retinal photoreceptor cells, which rely on the RPE for trophic support.
Wet AMD affects only 10%-15% of AMD patients, emerges abruptly and rapidly progresses to blindness. The advanced stage of the wet AMD is characterized by choroidal neovascularization (CNV), wherein new choroidal blood vessels emerge from the choroid toward the outer retina. Since the main pathology of wet AMD is the formation of new blood vessels, treatment of affected patients with anti-angiogenesis drugs have been proposed to reduce the risk of blindness. Accordingly, anti-angiogenic drugs such as bevacizumab and ranibizumab are commonly prescribed to treat for wet AMD, and which have been proven to halt the deterioration of vision and benefit many wet AMD patients.
Little is known about the growth factor and microenvironment mediating pathologic changes in early and advanced forms of dry AMD. In 2001, the Age-Related Eye Disease Study showed that daily high doses of the antioxidants beta-carotene, vitamins C and E, zinc, and copper decreased the risk of progression from early to advanced AMD in patients with intermediate forms of dry AMD (2). Other treatment strategies proposed for dry AMD include modulation of the visual cycle. By disrupting the conversion of retinol to rhodopsin, the key metabolite of phototransduction, toxic waste products such as lipofuscin and are decreased in the RPE (3). Proposed treatments to this end include ACU-4429 and fenretinide. Fenretinide is a synthetic retinoid derivative that competes with retinol in the circulation by binding retinol-binding protein. The ensuing complex is small enough to be excreted through the kidneys, thereby decreasing the available pool of retinol for uptake at the RPE. Additionally, International Patent Publication No. WO 2006/127945 discloses compounds and compositions that have been shown to reduce the formation of A2E. These compounds are designed to inhibit A2E biosynthesis by reducing the amount of free RAL available for reaction with PE in photoreceptor outer segments, which is the first step in the A2E biosynthetic pathway.
Other approaches for treating macular degeneration have been proposed, including use of neurotrophic receptor agonists, anti-inflammatory compounds including complement cascade inhibitors, anti-apoptosis compounds, steroids and anti-oxidant compounds (1). However, these and the other described treatments do not address the pathological cellular degeneration and senescence of the RPE cells that are most closely associated with the disease.
Similarities exist between AMD and Alzheimer's disease (AD). Both are neurodegenerative diseases, occurring at advancing age, both are associated with deposit formation such as amyloid (beta-amyloid) plaques in AD and drusen (beta-amyloid, apoE protein, complement components) in AMD. Additionally, both AMD and AD are associated with cellular senescence. The neurofibrillary tangles and neuritic components of the plaques of patients with AD show strong immunoreactivity for p16Ink4 (marker for senescence), but not for other members of this cell-cycle regulatory family. This biomarker of aging is not expressed in terminally differentiated neurons, demonstrating that the diseased neurons have acquired the expression of at least one senescence-associated protein. In AMD, markers of senescence, such as telomere shortening and altered gene expression have been identified in RPE cells exposed to advanced glycation end products (AGE), which are found in association with Bruch membrane in AMD. Moreover, in vitro studies in human RPE cell line, ARPE-19, revealed that exposure to oxidants resulted in four well known senescence markers, including hypertrophy, senescence-associated β-galactosidase (SA-β-galactosidase) activity, growth arrest and cell cycle arrest in G1/G0.
As described above, none of the current treatment approaches for AMD address the underlying cellular pathology of the disease. Likewise, AD continues to be a disease without an effective cure. Thus, a continuing need exists for treatments of senescence-related degenerative diseases including AMD and AD.